Folic acid is one of water-soluble vitamins, and is a co-enzyme necessary in the synthesis of amino acids or nucleic acids. Folic acid is converted to tetrahydrofolic acid by a reductase in the body, and then is further converted to be used in the synthesis of dTMP (deoxythymidine-1-phosphate) or purine. Folic acid derivatives include compounds that have a function of inhibiting the in vivo conversion of folic acid and thereby terminating cell division. A group of these compounds are called as folic acid antimetabolites, and methotrexate, which is a representative compound of the group, has long been used in the treatment of leukemia, sarcoma, stomach cancer and the like. Furthermore, methotrexate also has an immunomodulating action and thus serves as an essential drug for the chemotherapy of rheumatoid arthritis.
In addition, folic acid itself or a folic acid derivative such as leucovorin is also used as a drug for treating folic acid deficiency or neutralizing the toxicity of methotrexate.
As such, folic acid, or a folic acid derivative, for example, a folic acid antimetabolite which is represented by methotrexate, is a compound useful as a pharmaceutical product, and research on various derivatives is in progress for the purpose of improving the drug efficacy. Examples of these derivatives include aminopterin, pralatrexate, plevitrexed, edatrexate, pemetrexed, raltitrexed, lometrexol and the like, as shown below. The mode of action of these folic acid antimetabolites is mainly a dihydrofolate reductase inhibitory activity, but among the drugs newly developed, some even have a thymidylate synthetase inhibitory activity. Thus, there is a demand for more effective drugs, and development of those drugs is under way. For example, pemetrexed is characterized by inhibiting multiple enzymes involved in the folic acid metabolic system, and has been approved as a therapeutic drug for malignant pleural mesothelioma.

On the other hand, an experiment intended for the reduction of toxicity and enhancement of effects of low molecular weight drugs has been made as a part of the research on drug delivery systems (DDS). Various methods are available to achieve the object, for example, a drug may be bound to a polymer or may encapsulated in a nano-sized carrier. Regarding methotrexate, which is a compound representing folic acid derivatives, systems utilizing microspheres, dendrimers and micelles have been reported. However, none of the reports can be sufficiently satisfy the final purposes of the DDS research, that is, enhanced effects and reduced adverse side effects.
Patent Document 1 and Patent Document 3 describe water-soluble macromolecular pharmaceutical preparations containing, as a carrier, micelles formed by an amphiphilic polymer. Patent Document 1 describes, as an example of a hydrophobic segment, a polymer carrier having methotrexate bound thereto, but in this case, methotrexate and the amphiphilic polymer are linked via an amide bond. Patent Document 3 does not describe a polymer conjugate having folic acid or a folic acid derivative bound thereto.
Patent Document 2 reports that chemical stability and in vivo drug release efficiency can be simultaneously achieved by linking a polymer compound and a camptothecin compound via a phenyl ester bond. However, this method cannot be directly used for a carboxy group of a folic acid derivative (including folic acid itself), which is represented by methotrexate.
Furthermore, Non-Patent Document 1 and Non-Patent Document 2 describe polymer conjugates, which use a carboxy group of methotrexate to link methotrexate to an amphiphilic polymer via an alkyl ester bond. However, in this case, the release rate of drug is slow, and there arises a question on whether the effects of the drug would be exhibited. Furthermore, when the release of a drug from a polymer conjugate is dependent on the enzymes in vivo, there is a fear that the enzymatic activity, which varies between individuals, may cause variability in the drug release rate, and may consequently cause variability in the efficacy.